African Americans represent about 10% of the population in the US, but are under-represented in biomarker- related aging studies such as the Alzheimer's Disease Neuro-imaging Initiative (ADNI) and World Wide ADNI. Epidemiologic studies show that, compared to non-Hispanic white (NHW) Americans, African Americans are more likely to develop mild cognitive impairment (MCI) and Alzheimer's disease (AD), but may have slower rates of cognitive and functional decline. These point to the existence of an MCI/AD endophenotype for African Americans, but epidemiological studies without modern chemical or imaging biomarkers cannot differentiate between potential explanations for these observations, including vascular co-pathology, AD endophenotype, and neuroprotective anti-inflammatory mechanisms. Through a NIA-funded R21 (AG043885, PI: Hu), we have begun a cross-sectional study on race-dependent and race-independent factors associated with differences in AD biomarker profile between African Americans and NHW. In Project 1, we propose a longitudinal, multi-modal biomarker study to examine whether AD progression rates differ between the two races because of endothelial dysfunction, neuro-inflammation, or a true AD endophenotype. We will recruit the cross sectional cohort of 150 to undergo longitudinal biomarker analysis, and expand the cohort by 100 new subjects to account for more factors which may influence rates of AD progression. We will directly examine if 1) rates of cognitive decline in biomarker-confirmed cases of AD differ between African Americans and NHW, 2) endothelial dysfunction undergoes longitudinal change in African Americans and NHW, and 3) the interaction between AD and endothelial dysfunction is mediated through neuro-inflammation. In Aim 1, we will determine if African Americans subjects with AD biomarker profiles (CSF, MRI) experience slower cognitive decline than NHW subjects with the same AD biomarker profiles. In Aim 2, we will determine if African Americans subjects undergo greater longitudinal change in endothelial dysfunction than NHW subjects, using CSF levels of novel endothelial markers and MRI analysis of cerebral blood flow, axonal integrity, and cerebral microbleeds. In Aim 3, we will model the interaction between longitudinal AD and endothelial marker profiles, and test the hypothesis that African Americans subjects with AD biomarker profiles are more likely to have an anti-inflammatory CSF profile than NHW subjects with the same AD biomarker profiles. Successful completion of these aims will create a modern biomarker-rich dataset consisting of equal proportions of African Americans and NHW seniors, construct the first progression profiles of modern AD and endothelial markers in African Americans seniors, identify whether longitudinal changes in CSF and MRI AD biomarkers differ between African Americans and NHW, and set the stage for a multi-center, multi-modal biomarker study involving African Americans and NHW seniors.